Induction and inhibition of cytochrome P450 isoforms by imazalil, a food contaminant, in mouse small intestine and liver.
1. The effects of imazalil, a food contaminant used as a fungicide, were investigated on the expression and activity of cytochrome P450 in the small intestinal mucosa and liver of mice. Imazalil was orally administered to mice daily at 1 or 10 mg/kg for 3 days. 2. Imazalil enhanced cytochrome P450-catalysed ethoxyresorufin O-deethylase and pentoxyresorufin O-depentylase (PROD) activities in both tissue microsomes at the 10 mg/kg/day dose level, indicating the induction of cytochrome P450 subfamilies CYP1A and CYP2B. In addition, immunochemical analyses also demonstrated an enhanced expression of CYP2B, CYP2C and CYP3A subfamilies in both tissues. 3. Imazalil was a potent inhibitor of cytochrome P450-dependent monooxygenase activities (PROD, aminopyrine N-demethylase and erythromycin demethylase) in in vitro assays using both small intestinal and liver microsomes. 4. From these findings, imazalil has been demonstrated to have not only a potent inhibitory activity but also a significant inducing ability of P450 isoforms in the small intestine. Prolonged ingestion of such a food contaminant may modulate the xenobiotic-metabolizing enzyme system at the site of a primary portal of xenobiotic entry to the systemic circulation.
Muto
N
N
Department of Environmental Toxicology, Faculty of Pharmaceutical Sciences, Osaka University, Japan.
Hirai
H
H
Tanaka
T
T
Itoh
N
N
Tanaka
K
K
D000818:Animals; D015153:Blotting, Western; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005506:Food Contamination / Q000032:analysis*; D005659:Fungicides, Industrial / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology
D065607:Cytochrome P-450 Enzyme Inhibitors; D005659:Fungicides, Industrial; D007093:Imidazoles; D007527:Isoenzymes; C017435:enilconazole; D003577:Cytochrome P-450 Enzyme System